The following discussion of the background art is intended to facilitate an understanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge as at the priority date of the application.
Peptides, and in particular polypeptides such as proteins, are increasingly becoming recognised as desirable agents for the treatment of diseases manifesting in the gut (gastrointestinal tract). Protein therapeutics are often based on natural products with a long history of medicinal use, which have a higher safety profile than small molecules that have been newly synthesised and whose effects on the body are largely unknown. Also, proteins can exhibit a high degree of specificity and selectivity, and at the same time can be designed to take advantage of their large size to display multi-functionality, enabling them to interact concurrently with two or more different targets.
Proteins with antioxidant activity, such as superoxide dismutase, are examples of such therapeutic applications. Other examples are monoclonal antibodies, which can act as anti-infectives by binding to sites on infectious organisms invading the gut. Alternatively, such antibodies can bind to receptor sites on intestinal cells, and interfere with adhesion processes and the colonisation of infectious organisms. In addition, these antibodies can interact with cells of the immune system to stimulate their activity in combating infectious diseases. Other types of therapeutic peptides include peptide hormones, such as appetite suppressing agents.
One important drawback to the use of peptides in the intestine is their extreme sensitivity to gut proteases. These proteases can be found both in the stomach (e.g. pepsin), and in the upper intestine, and have evolved to enable the digestive tract to break down peptides ingested as food, by proteolysis, into amino acids which can be taken up as nutrients by receptor-mediated mechanisms.
If the intended site of action of a therapeutic or prophylactic peptide is the small intestine, then the peptide can be protected from breakdown in the stomach by placing it inside an enteric-coated capsule, tablet or other device which resists dissolution at the low pH found in the stomach, but disintegrates at higher pH to release the peptide into the small intestine, e.g. the duodenum, jejunum or ileum. However, the action of the proteases found in the small intestine (in particular the serine proteases, trypsin, chymotrypsin, elastase and carboxypeptidase) is such that they can rapidly break down and destroy peptides once they have been released from such a device. This clearly limits the efficacy of orally administered therapeutic peptides, and a means of preventing their degradation by proteases would markedly enhance their performance.
Although there are many agents acting as protease inhibitors that are known to those skilled in the art, few, if any, are appropriate for this particular application. Most known inhibitors, e.g. antipain, leupeptin, are used for research purposes only, and are not acceptable for human administration. Some inhibitors, e.g diisopropyl fluorophosphate or phenylmethyl sulphonyl fluoride have a high degree of potency, but display a very broad specificity, so there is a risk of their exerting their action in undesirable parts of the body, in addition to the gut. On the other hand, other inhibitors, such as the new class of protease inhibitors employed in the treatment of HIV, are so selective in the nature of the proteases they inhibit that they have no effect on serine proteases in the gut. Two serine protease inhibitors that have been administered to humans are aprotinin and soybean trypsin inhibitor. However; these are relatively expensive to synthesise, and would have to be included in a medicament at such high levels that the cost of the final product would prohibit the manufacture of a medicament for routine daily use.
The present invention seeks to address or at least ameliorate one or more the problems associated with prior art devices.